Diffuse demyelination disorders affect more than one-quarter million of Americans and are associated with a wide range of clinical manifestations. They can occur due to chronic alcoholism and malnourishment, inflammatory processes, viral infection, hypoxic-ischemic injury, focal depression, metabolic dysfunction and as we show in our own work, by exposure to environmental toxicants and chemotherapeutic agents. Another class of diseases that are distinct from demyelination are those in which there is a failure to form myelin, resulting in hypomyelination. A large number of hypomyelinations are a consequence of insults to the developing brain and most frequently occur in children. Hypomyelination is often associated with lower IQ, delayed or impaired verbal skills and social and behavioral abnormalities and has been described to be associated with autism, attention deficit/hyperactivity disorder, psychosis and schizophrenia. The diagnostic study of demyelinating and hypomyelinating disorders is severely hampered by the difficulty to diagnose such diseases prior to the onset of severe clinical symptoms, as current diagnostic tools such as magnetic resonance imaging or histopathological analysis are either limited in their sensitivity and costly, or require invasive methods, that generate only confirmatory results. We propose to provide the basis for the development of a new approach that allows the early diagnosis and intervention for de- and hypomyelinating disorders using the highly sensitive auditory system as a functional readout. We will characterize the impact of mechanism by which target cells in the auditory system respond to the insults and use this new approach to determine the efficacy of therapeutic interventions that are designed to restore auditory nerve conduction specifically and proper myelination in the brain in general.
The central hypothesis of this application is that impairment of myelination, irrespective of the mechanisms, can be diagnosed and characterized by utilizing auditory brain stem recordings and analysis as a sensitive and non-invasive diagnostic tool. We focus on two myelin disorders: demyelination caused by exposure to chemotherapeutic agents and hypomyelination as a result of being born to a mother who suffered iron deficiency during pregnancy. We propose experiments that will identify the cell populations that are associated with neural conduction deficits in the auditory system, we will determine whether the auditory system can be used as a novel diagnostic too diffuse myelination impairment and will identify rescue strategies that have clinical relevance.
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